Therapy with combined interferon and ribavirin has led to clinical improvement for some patients with chronic HCV infection. Although further treatment improvements have been achieved with pegylated-interferon and ribavirin, viral replication is incompletely inhibited with a high relapse rate when patients discontinue treatment. Therapeutic human monoclonal antibodies (HMAbs) are an approach to address the limitations of current therapy for HCV infection. Accumulating studies and preliminary findings with a large panel of IgG HCV HMAbs support the feasibility of this approach. To achieve this goal, one concern for HCV is that a significant fraction of infectious virions are lipid coated. The view is that low density lipoprotein (LDL) coating of virions may limit the availability of HCV envelope proteins E1 and E2 for recognition by specific antibodies (Abs). Based on preliminary studies with HCV HMAbs, we believe that certain HCV E1 and E2 sites remain available to Abs on LDL-coated virions. Based on our previous studies, we hypothesize that specific HMAbs to E1 and E2 epitopes that mediate virion entry into target cells are more effective in suppressing viral infection than Abs that recognize other structural components of the virion surface. Other concerns are the theoretical possibility of HMAb mediated enhancement of infection and emergence of escape mutants of HCV resistant to HMAbs. The recent breakthroughs in establishing human cell lines that support persistent HCV infection and produce infectious virions have opened the route to detailed functional characterization of our HMAbs and development of novel HMAb variants that with improved virus neutralization (Vn) activity. The objectives of this project are to systematically determine the interrelationship of key parameters hypothesized to impact HCV Vn and develop new generation therapeutic Abs with improved Vn activity. Development of higher affinity analogs of the HMAbs is proposed as the means for improved neutralization, as HMAbs with improved HCV binding strength are likely to provide more stable protection from infection. Recent technological developments in the field of catalytic Abs have rendered feasible the development of Abs that specifically cleave HCV E1 and E2 proteins. Development of such catalytic Abs from our HMAbs is proposed by a subunit shuffling approach. The catalytic Abs can potentially neutralize HCV by recognizing a broader range of epitopes than conventional Abs, as cleavage of even functionally unimportant HCV sites should induce major conformational transitions in the product fragments. Moreover, the catalytic function should impart multi-hit capability to the HMAbs, as a single catalyst molecule is reused to cleave multiple molecules of the viral target.